The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Astrocytomas

Cudaback, Eiron; Marrs, William R.; Möeller, Thomas; Stella, Nephi

doi:10.1371/journal.pone.0008702

Cited by 73 publications

(79 citation statements)

References 41 publications

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“…Nonetheless, a tumour-promoting effect of cannabinoids has been proposed in a few reports (Cudaback et al, 2010;Hart et al, 2004;McKallip et al, 2005;Zhu et al, 2000).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…16 tumour-promoting immunosuppressive role of cannabinoids (Cudaback et al, 2010;Hart et al, 2004;McKallip et al, 2005;Zhu et al, 2000) a large body of scientific evidences strongly support THC and other cannabinoid agonists exert anticancer actions in preclinical models of cancer (including immunocompetent mice) through a wellestablished mechanism of action. There is also a good evidence of that cannabinoids enhance the anticancer activity of TMZ and ALK inhibitors in animal models of glioma.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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The use of cannabinoids as anticancer agents

Velasco

Hernández-Tiedra

Dávila

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

140

101

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It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.

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“…Nonetheless, a tumour-promoting effect of cannabinoids has been proposed in a few reports (Cudaback et al, 2010;Hart et al, 2004;McKallip et al, 2005;Zhu et al, 2000).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

The use of cannabinoids as anticancer agents

Velasco

Hernández-Tiedra

Dávila

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

140

101

View full text Add to dashboard Cite

show abstract

“…However, in this study, reductions in CB 1 receptor density were not associated with the characteristic neuropathological hallmarks of AD. Recent findings from Cudaback et al (79) suggest that cannabinoid receptor expression may determine their efficacy for activating proapoptotic and prosurvival signals, whereby low levels of cannabinoid receptor expression in astrocytoma subclones couple to apoptotic pathways, whereas high levels of expression also couple to prosurvival pathways. Thus, it is a possibility that endocannabinoids have a direct modulating effect on the expression of cannabinoid receptors, which in turn couple to prosurvival signaling pathways to confer neuroprotection.…”

Section: Endocannabinoids Prevent the A␤-induced Up-regulation Of P-p53mentioning

confidence: 99%

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Noonan

Tanveer

Klompas

et al. 2010

Journal of Biological Chemistry

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Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD).Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by ␤-amyloid (A␤) is thus important for the development of therapeutic strategies that can thwart A␤ toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by A␤. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against A␤-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the A␤-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against A␤ toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection. Alzheimer disease (AD)2 is a debilitating illness of the brain defined by the progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and surrounding areas of the cerebral cortex (1). There is substantial evidence to suggest that at least a subset of neurons in the AD brain die by apoptosis (2). The principal neuropathological hallmark of the disease, ␤-amyloid peptide (A␤), has been shown to induce apoptosis in neuronal cells in vivo and in vitro (3, 4) through a variety of enzymatic pathways that include activation of caspase-3 (5), calpain (6, 7), and lysosomal cathepsins (8, 9).Recently, the lysosomal system has been implicated in AD pathogenesis (9, 10). Neurons of AD patients demonstrate alterations in the lysosomal system, including the cellular pathways that converge on it, namely endocytosis and autophagy (10, 11). Such alterations include an increase in the size and number of endosomes (10, 12), autophagosomes (13) and lysosomes (10) and an increase in the gene expression and synthesis of all classes of lysosomal hydrolases, including cathepsins (14). In addition to their role in the digestion of cellular waste, it has become clear that partial and selective lysosomal membrane permeabilization (LMP), followed by the release of lysosomal enzymes into the cytosol, can induce apoptotic cell death (15). Cathepsins D and L are among the lysosomal proteases that have been implicated in apoptosis by virtue of their ability to activate apoptotic effectors, such as mitochondrial uncoupling and caspases (16).Among the agents that are ca...

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“…29 All fluorescence images taken are confocal-like images using a Zeiss Axio Observer fluorescence microscope equipped with the ApoTome 2 imaging system. Figure 5(a) shows fluorescence images of CB 2 -mid DBT cells and WT DBT-cells (non-CB 2 R expressing control) after incubation with 5 μM of ZW760-mbc94, ZW760-mbc94 þ 4-Quinolone-3-Carboxamide (4Q3C, blocking agent), or ZW760 (free dye control) for 30 min at 37°C…”

Section: Resultsmentioning

confidence: 99%

Targeted zwitterionic near infrared fluorescent probe for improved imaging of type 2 cannabinoid receptors

Shao

Zhang

et al. 2014

J. Biomed. Opt

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Abstract. Recent studies indicate that the type 2 cannabinoid receptors (CB 2 R) have become an attractive target for treating a variety of pathologies, including cancers, neurodegenerative diseases, inflammation, pain, osteoporosis, immunological disorders and drug abuse. In addition, it appears that many of these diseases have up-regulated CB 2 R expression. However, the precise role of CB 2 R in the regulation of diseases remains unclear. The ability to specifically image CB 2 R would contribute to develop reliable CB 2 R-based therapeutic approaches with a better understanding of the mechanism of CB 2 R action in these diseases. We developed a CB 2 R-targeted zwitterionic near-infrared (NIR) fluorescent probe, ZW760-mbc94. When compared with a previously reported CB 2 R probe (NIR760-mbc94) with the same targeting moiety but a charged NIR fluorescent dye, ZW760-mbc94 showed improved binding specificity in vitro and ex vivo. Overall, ZW760-mbc94 appears to have great potential as a CB 2 R-targeted contrast agent.

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The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Astrocytomas

Cited by 73 publications

References 41 publications

The use of cannabinoids as anticancer agents

The use of cannabinoids as anticancer agents

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Targeted zwitterionic near infrared fluorescent probe for improved imaging of type 2 cannabinoid receptors

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